The work is directed toward the design of compounds, in particular nucleotide derivatives, which would inhibit an isozyme isolated from neoplastic tissue without affecting the substrate-identical isozyme isolated from normal host tissue. In a systematic approach toward such tumor tissue-specific enzyme inhibitors, the contact points of nucleotide substrates with candidate enzymes will be determined by removal of or substitution on probable binding atoms of the substrate, after which substituent tolerance within enzyme-substrate complexes will be investigated by the introduction of small groups at various positions on the substrates. The usefulness of such substrate substituents for the design of species- and isozyme-selective enzyme inhibitors will be studied.